Treatment of cancer with dnapk inhibitors

ABSTRACT

Provided herein are methods for treating or preventing Wnt-associated cancers, comprising administering an effective amount of a DNAPK inhibitor to a patient having a Wnt-associated cancer.

This application claims the benefit of priority to U.S. ProvisionalApplication Ser. No. 62/183,920, filed Jun. 24, 2015, which isincorporated herein by reference in its entirety and for all purposes.

1. FIELD

Provided herein are methods for treating or preventing Wnt-associatedcancers, comprising administering an effective amount of a DNAPKinhibitor to a patient having a Wnt-associated cancer.

2. BACKGROUND

Kinases play a vital role in driving oncogenic pathways and have beenthe mainstay in the development of therapeutics across multiple cancers(Rask-Andersen, M., et al., Advances in kinase targeting: currentclinical use and clinical trials. Trends Pharmacol Sci, 2014. 35(11): p.604-20; Zhang, J., P. L. Yang, and N. S. Gray, Targeting cancer withsmall molecule kinase inhibitors. Nat Rev Cancer, 2009. 9(1): p. 28-39).

DNAPK, a nuclear serine/threonine protein kinase, has been known for itsrole in DNA repair via the non-homologous end joining (NHEJ) pathway.However, emerging studies indicate the importance of DNAPK in a varietyof other processes, including the modulation of chromatin structure andtranscription through its interaction with a variety of receptors andtranscription factors (Munoz, D. P., M. Kawahara, and S. M. Yannone, Anautonomous chromatin/DNA-PK mechanism for localized DNA damage signalingin mammalian cells. Nucleic Acids Res, 2013. 41(5): p. 2894-906; Pyun,B. J., et al., Mutual regulation between DNA-PKcs and Snail1 leads toincreased genomic instability and aggressive tumor characteristics. CellDeath Dis, 2013. 4: p. e517; Brenner, J. C., et al., Mechanisticrationale for inhibition of poly(ADP-ribose) polymerase in ETS genefusion-positive prostate cancer. Cancer Cell, 2011. 19(5): p. 664-78;An, J., et al., Downregulation of c-myc protein by siRNA-mediatedsilencing of DNA-PKcs in HeLa cells. Int J Cancer, 2005. 117(4): p.531-7; Achanta, G., et al., Interaction of p53 and DNA-PK in response tonucleoside analogues: potential role as a sensor complex for DNA damage.Cancer Res, 2001. 61(24): p. 8723-9; Bandyopadhyay, D., et al., Physicalinteraction between epidermal growth factor receptor and DNA-dependentprotein kinase in mammalian cells. J Biol Chem, 1998. 273(3): p.1568-73). More recently, in the context of prostate cancer, it wasdemonstrated that DNAPK can also transcriptionally activate the androgenreceptor, potentiates AR function and thus represents a potentialtherapeutic target in CRPC (Goodwin, J. F., et al., A hormone-DNA repaircircuit governs the response to genotoxic insult. Cancer Discov, 2013.3(11): p. 1254-71). However, if the role of DNAPK in prostate cancerprogression is just to stimulate the androgen receptor, thenandrogen-directed therapies should also suppress the oncogenic role ofDNAPK. Given that DNAPK expression is strongly associated withmetastatic CRPC progression, it is clear that DNAPK plays additionalimportant roles in activating compensatory signaling pathwaysresponsible for bypassing the conventional androgen-directed therapies.

The embodiments provided herein are based on the discovery of a novelrole of DNAPK in regulating Wnt signaling, a mechanism which is known toplay oncogenic roles across multiple cancers, including CRPC. Thisdiscovery demonstrates a need for compounds useful for treatingWnt-associated cancers.

Citation or identification of any reference in Section 2 of thisapplication is not to be construed as an admission that the reference isprior art to the present application.

3. SUMMARY

Provided herein are methods for treating or preventing Wnt-associatedcancers, comprising administering an effective amount of a DNAPKinhibitor to a patient having Wnt-associated cancer.

Further provided herein are methods for inhibiting or preventingmetastasis of Wnt-associated cancers, comprising administering aneffective amount of a DNAPK inhibitor to a patient having aWnt-associated cancer.

Further provided herein are methods for inhibiting or preventingexpansion or survival of cancer stem cells of Wnt-associated cancers,comprising contacting the cancer stem cells of a Wnt-associated cancerwith an effective amount of a DNAPK inhibitor.

Further provided herein are methods for inhibiting or preventingexpansion or survival of resistant and/or refractory tumor cells ofWnt-associated cancers, comprising contacting the tumor cells of theWnt-associated cancer with an effective amount of a DNAPK inhibitor.

Further provided herein are methods for treating or preventing androgendeprivation therapy (ADT)-resistant cancers, comprising administering aneffective amount of a DNAPK inhibitor to a patient having an androgendeprivation therapy-resistant cancer.

Further provided herein are methods for preventing androgen deprivationtherapy resistance in cancers, comprising administering an effectiveamount of a DNAPK inhibitor to a patient having cancer.

Further provided herein are methods for treating or preventingenzalutamide-resistant cancers, comprising administering an effectiveamount of a DNAPK inhibitor to a patient having anenzalutamide-resistant cancer.

Further provided herein are methods for detecting or measuring theinhibition of DNAPK activity in a patient, comprising measuringdecreased phosphorylation of a DNAPK substrate (such as DNAPK or Hsp90a)in a biological sample from said patient, for example a peripheral bloodor tumor sample, prior to and after the administration of a DNAPKinhibitor to said patient.

Further provided herein are methods for detecting or measuring theeffect of inhibition of DNAPK activity on markers of Wnt activity in apatient, comprising measuring markers of Wnt activity in a biologicalsample from said patient, for example a peripheral blood or tumorsample, prior to and after the administration of a DNAPK inhibitor tosaid patient.

Also provided herein are methods for predicting the likelihood of acancer of a patient being responsive to DNAPK inhibitor therapy,comprising: screening a biological sample of said patient for markers ofWnt activity, wherein the presence of markers of Wnt activity indicatesan increased likelihood that a cancer of said patient will be responsiveto DNAPK inhibitor therapy.

Further provided herein are methods for determining whether a patient issensitive to a DNAPK inhibitor, comprising administering said patientsaid DNAPK inhibitor and determining whether markers of Wnt activity{[5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid aremodulated in said patient by measuring the markers of Wnt activity in abiological sample from said patient, for example a peripheral blood ortumor sample, prior to and after the administration of the DNAPKinhibitor to said patient.

Also provided herein is a kit for detecting markers of Wnt activitycomprising reagents for measuring markers of Wnt activity and one ormore DNAPK inhibitors.

In some embodiments, the DNAPK inhibitor is a compound as describedherein.

In some embodiments, the methods described herein, additionally compriseadministration of a Wnt pathway modulator, a Wnt inhibitor, and/or anandrogen receptor antagonist, as described herein.

The present embodiments can be understood more fully by reference to thedetailed description and examples, which are intended to exemplifynon-limiting embodiments.

4. DETAILED DESCRIPTION 4.1 Definitions

An “alkyl” group is a saturated, partially saturated, or unsaturatedstraight chain or branched non-cyclic hydrocarbon having from 1 to 10carbon atoms, typically from 1 to 8 carbons or, in some embodiments,from 1 to 6, 1 to 4, or 2 to 6 or carbon atoms. Representative alkylgroups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and-n-hexyl; while saturated branched alkyls include -isopropyl,-sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl and the like. Examplesof unsaturared alkyl groups include, but are not limited to, vinyl,allyl, —CH═CH(CH₃), —CH═C(CH₃)₂, —C(CH₃)═CH₂, —C(CH₃)═CH(CH₃),—C(CH₂CH₃)═CH₂, —C≡CH, —C≡C(CH₃), —C≡C(CH₂CH₃), —CH₂C≡CH, —CH₂C≡C(CH₃)and —CH₂C≡C(CH₂CH₃), among others. An alkyl group can be substituted orunsubstituted. In certain embodiments, when the alkyl groups describedherein are said to be “substituted,” they may be substituted with anysubstituent or substituents as those found in the exemplary compoundsand embodiments disclosed herein, as well as halogen (chloro, iodo,bromo, or fluoro); hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino;carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine;guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine;thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester;urea; urethane; oxime; hydroxyl amine; alkoxyamine; aralkoxyamine;N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate;isothiocyanate; cyanate; thiocyanate; B(OH)₂, or O(alkyl)aminocarbonyl.

An “alkenyl” group is a straight chain or branched non-cyclichydrocarbon having from 2 to 10 carbon atoms, typically from 2 to 8carbon atoms, and including at least one carbon-carbon double bond.Representative straight chain and branched (C₂-C₈)alkenyls include-vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl,-2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl,-2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl, -3-hexenyl,-1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl, -2-octenyl,-3-octenyl and the like. The double bond of an alkenyl group can beunconjugated or conjugated to another unsaturated group. An alkenylgroup can be unsubstituted or substituted.

A “cycloalkyl” group is a saturated, or partially saturated cyclic alkylgroup of from 3 to 10 carbon atoms having a single cyclic ring ormultiple condensed or bridged rings which can be optionally substitutedwith from 1 to 3 alkyl groups. In some embodiments, the cycloalkyl grouphas 3 to 8 ring members, whereas in other embodiments the number of ringcarbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. Such cycloalkylgroups include, by way of example, single ring structures such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl,2-methylcyclooctyl, and the like, or multiple or bridged ring structuressuch as adamantyl and the like. Examples of unsaturared cycloalkylgroups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl,pentadienyl, hexadienyl, among others. A cycloalkyl group can besubstituted or unsubstituted. Such substituted cycloalkyl groupsinclude, by way of example, cyclohexanone and the like.

An “aryl” group is an aromatic carbocyclic group of from 6 to 14 carbonatoms having a single ring (e.g., phenyl) or multiple condensed rings(e.g., naphthyl or anthryl). In some embodiments, aryl groups contain6-14 carbons, and in others from 6 to 12 or even 6 to 10 carbon atoms inthe ring portions of the groups. Particular aryls include phenyl,biphenyl, naphthyl and the like. An aryl group can be substituted orunsubstituted. The phrase “aryl groups” also includes groups containingfused rings, such as fused aromatic-aliphatic ring systems (e.g.,indanyl, tetrahydronaphthyl, and the like).

A “heteroaryl” group is an aryl ring system having one to fourheteroatoms as ring atoms in a heteroaromatic ring system, wherein theremainder of the atoms are carbon atoms. In some embodiments, heteroarylgroups contain 5 to 6 ring atoms, and in others from 6 to 9 or even 6 to10 atoms in the ring portions of the groups. Suitable heteroatomsinclude oxygen, sulfur and nitrogen. In certain embodiments, theheteroaryl ring system is monocyclic or bicyclic. Non-limiting examplesinclude but are not limited to, groups such as pyrrolyl, pyrazolyl,imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl,pyrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl,benzothiophenyl, furanyl, benzofuranyl (for example,isobenzofuran-1,3-diimine), indolyl, azaindolyl (for example,pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl(for example, 1H-benzo[d]imidazolyl), imidazopyridyl (for example,azabenzimidazolyl, 3H-imidazo[4,5-b]pyridyl or1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl,benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl,guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl,and quinazolinyl groups.

A “heterocyclyl” is an aromatic (also referred to as heteroaryl) ornon-aromatic cycloalkyl in which one to four of the ring carbon atomsare independently replaced with a heteroatom from the group consistingof O, S and N. In some embodiments, heterocyclyl groups include 3 to 10ring members, whereas other such groups have 3 to 5, 3 to 6, or 3 to 8ring members. Heterocyclyls can also be bonded to other groups at anyring atom (i.e., at any carbon atom or heteroatom of the heterocyclicring). A heterocyclylalkyl group can be substituted or unsubstituted.Heterocyclyl groups encompass unsaturated, partially saturated andsaturated ring systems, such as, for example, imidazolyl, imidazolinyland imidazolidinyl groups. The phrase heterocyclyl includes fused ringspecies, including those comprising fused aromatic and non-aromaticgroups, such as, for example, benzotriazolyl,2,3-dihydrobenzo[1,4]dioxinyl, and benzo[1,3]dioxolyl. The phrase alsoincludes bridged polycyclic ring systems containing a heteroatom suchas, but not limited to, quinuclidyl. Representative examples of aheterocyclyl group include, but are not limited to, aziridinyl,azetidinyl, pyrrolidyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl,tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl,pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl,isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl,morpholinyl, thiomorpholinyl, tetrahydropyranyl (for example,tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathiane, dioxyl,dithianyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl,triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodithionyl,homopiperazinyl, quinuclidyl, indolyl, indolinyl, isoindolyl, azaindolyl(pyrrolopyridyl), indazolyl, indolizinyl, benzotriazolyl,benzimidazolyl, benzofuranyl, benzothiophenyl, benzthiazolyl,benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl,benzothiazinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[1,3]dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl;for example, 1H-imidazo[4,5-b]pyridyl, or1H-imidazo[4,5-b]pyridin-2(3H)-onyl), triazolopyridyl, isoxazolopyridyl,purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl,quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl,naphthyridinyl, pteridinyl, thianaphthalenyl, dihydrobenzothiazinyl,dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl,tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl,tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl,tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl,tetrahydrotriazolopyridyl, and tetrahydroquinolinyl groups.Representative substituted heterocyclyl groups may be mono-substitutedor substituted more than once, such as, but not limited to, pyridyl ormorpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, ordisubstituted with various substituents such as those listed below.

A “cycloalkylalkyl” group is a radical of the formula:-alkyl-cycloalkyl, wherein alkyl and cycloalkyl are defined above.Substituted cycloalkylalkyl groups may be substituted at the alkyl, thecycloalkyl, or both the alkyl and the cycloalkyl portions of the group.Representative cycloalkylalkyl groups include but are not limited tocyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl,and cyclohexylpropyl. Representative substituted cycloalkylalkyl groupsmay be mono-substituted or substituted more than once.

An “aralkyl” group is a radical of the formula: -alkyl-aryl, whereinalkyl and aryl are defined above. Substituted aralkyl groups may besubstituted at the alkyl, the aryl, or both the alkyl and the arylportions of the group. Representative aralkyl groups include but are notlimited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkylgroups such as 4-ethyl-indanyl.

A “heterocyclylalkyl” group is a radical of the formula:-alkyl-heterocyclyl, wherein alkyl and heterocyclyl are defined above.Substituted heterocyclylalkyl groups may be substituted at the alkyl,the heterocyclyl, or both the alkyl and the heterocyclyl portions of thegroup. Representative heterocylylalkyl groups include but are notlimited to 4-ethyl-morpholinyl, 4-propylmorpholinyl, furan-2-yl methyl,furan-3-yl methyl, pyrdine-3-yl methyl,(tetrahydro-2H-pyran-4-yl)methyl, (tetrahydro-2H-pyran-4-yl)ethyl,tetrahydrofuran-2-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-ylpropyl.

A “halogen” is chloro, iodo, bromo, or fluoro.

A “hydroxyalkyl” group is an alkyl group as described above substitutedwith one or more hydroxy groups.

An “alkoxy” group is —O-(alkyl), wherein alkyl is defined above.

An “alkoxyalkyl” group is -(alkyl)-O-(alkyl), wherein alkyl is definedabove.

An “amine” group is a radical of the formula: —NH₂.

A “hydroxyl amine” group is a radical of the formula: —N(R^(#))OH or—NHOH, wherein R^(#) is a substituted or unsubstituted alkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl orheterocyclylalkyl group as defined herein.

An “alkoxyamine” group is a radical of the formula: —N(R^(#))O-alkyl or—NHO-alkyl, wherein R^(#) is as defined above.

An “aralkoxyamine” group is a radical of the formula: —N(R^(#))O-aryl or—NHO-aryl, wherein R^(#) is as defined above.

An “alkylamine” group is a radical of the formula: —NH-alkyl or—N(alkyl)₂, wherein each alkyl is independently as defined above.

An “aminocarbonyl” group is a radical of the formula: —C(═O)N(R^(#))₂,—C(═O)NH(R^(#)) or —C(═O)NH₂, wherein each R^(#) is as defined above.

An “acylamino” group is a radical of the formula: —NHC(═O)(R^(#)) or—N(alkyl)C(═O)(R^(#)), wherein each alkyl and R^(#) are independently asdefined above.

An “O(alkyl)aminocarbonyl” group is a radical of the formula:—O(alkyl)C(═O)N(R^(#))₂, —O(alkyl)C(═O)NH(R^(#)) or —O(alkyl)C(═O)NH₂,wherein each R^(#) is independently as defined above.

An “N-oxide” group is a radical of the formula: —N⁺—O⁻.

A “carboxy” group is a radical of the formula: —C(═O)OH.

A “ketone” group is a radical of the formula: —C(═O)(R^(#)), whereinR^(#) is as defined above.

An “aldehyde” group is a radical of the formula: —CH(═O).

An “ester” group is a radical of the formula: —C(═O)O(R^(#)) or—OC(═O)(R^(#)), wherein R^(#) is as defined above.

A “urea” group is a radical of the formula: —N(alkyl)C(═O)N(R^(#))₂,—N(alkyl)C(═O)NH(R^(#)), —N(alkyl)C(═O)NH₂, —NHC(═O)N(R^(#))₂,—NHC(═O)NH(R^(#)), or —NHC(═O)NH₂#, wherein each alkyl and R^(#) areindependently as defined above.

An “imine” group is a radical of the formula: —N═C(R^(#))₂ or—C(R^(#))═N(R^(#)), wherein each R^(#) is independently as definedabove.

An “imide” group is a radical of the formula: —C(═O)N(R^(#))C(═O)(R^(#))or —N((C═O)(R^(#)))₂, wherein each R^(#) is independently as definedabove.

A “urethane” group is a radical of the formula: —OC(═O)N(R^(#))₂,—OC(═O)NH(R^(#)), —N(R^(#))C(═O)O(R^(#)), or —NHC(═O)O(R^(#)), whereineach R^(#) is independently as defined above.

An “amidine” group is a radical of the formula: —C(═N(R^(#)))N(R^(#))₂,—C(═N(R^(#)))NH(R^(#)), —C(═N(R^(#)))NH₂, —C(═NH)N(R^(#))₂,—C(═NH)NH(R^(#)), —C(═NH)NH₂, —N═C(R^(#))N(R^(#))₂,—N═C(R^(#))NH(R^(#)), —N═C(R^(#))NH₂, —N(R^(#))C(R^(#))═N(R^(#)),—NHC(R^(#))═N(R^(#)), —N(R^(#))C(R^(#))═NH, or —NHC(R^(#))═NH, whereineach R^(#) is independently as defined above.

A “guanidine” group is a radical of the formula:—N(R^(#))C(═N(R^(#)))N(R^(#))₂, —NHC(═N(R^(#)))N(R^(#))₂,—N(R^(#))C(═NH)N(R^(#))₂, —N(R^(#))C(═N(R^(#)))NH(R^(#)),—N(R^(#))C(═N(R^(#)))NH₂, —NHC(═NH)N(R^(#))₂, —NHC(═N(R^(#)))NH(R^(#)),—NHC(═N(R^(#)))NH₂, —NHC(═NH)NH(R^(#)), —NHC(═NH)NH₂, —N═C(N(R^(#))₂)₂,—N═C(NH(R^(#)))₂, or —N═C(NH₂)₂, wherein each R^(#) is independently asdefined above.

A “enamine” group is a radical of the formula:—N(R^(#))C(R^(#))═C(R^(#))₂, —NHC(R^(#))═C(R^(#))₂,—C(N(R^(#))₂)═C(R^(#))₂, —C(NH(R^(#)))═C(R^(#))₂, —C(NH₂)═C(R^(#))₂,—C(R^(#))═C(R^(#))(N(R^(#))₂), —C(R^(#))═C(R^(#))(NH(R^(#))) or—C(R^(#))═C(R^(#))(NH₂), wherein each R^(#) is independently as definedabove.

An “oxime” group is a radical of the formula: —C(═NO(R^(#)))(R^(#)),—C(═NOH)(R^(#)), —CH(═NO(R^(#))), or —CH(═NOH), wherein each R^(#) isindependently as defined above.

A “hydrazide” group is a radical of the formula:—C(═O)N(R^(#))N(R^(#))₂, —C(═O)NHN(R^(#))₂, —C(═O)N(R^(#))NH(R^(#)),—C(═O)N(R^(#))NH₂, —C(═O)NHNH(R^(#))₂, or —C(═O)NHNH₂, wherein eachR^(#) is independently as defined above.

A “hydrazine” group is a radical of the formula: —N(R^(#))N(R^(#))₂,—NHN(R^(#))₂, —N(R^(#))NH(R^(#)), —N(R^(#))NH₂, —NHNH(R^(#))₂, or—NHNH₂, wherein each R^(#) is independently as defined above.

A “hydrazone” group is a radical of the formula:—C(═N—N(R^(#))₂)(R^(#))₂, —C(═N—NH(R^(#)))(R^(#))₂, —C(═N—NH₂)(R^(#))₂,—N(R^(#))(N═C(R^(#))₂), or —NH(N═C(R^(#))₂), wherein each R^(#) isindependently as defined above.

An “azide” group is a radical of the formula: —N₃.

An “isocyanate” group is a radical of the formula: —N═C═O.

An “isothiocyanate” group is a radical of the formula: —N═C═S.

A “cyanate” group is a radical of the formula: —OCN.

A “thiocyanate” group is a radical of the formula: —SCN.

A “thioether” group is a radical of the formula; —S(R^(#)), whereinR^(#) is as defined above.

A “thiocarbonyl” group is a radical of the formula: —C(═S)(R^(#)),wherein R^(#) is as defined above.

A “sulfinyl” group is a radical of the formula: —S(═O)(R^(#)), whereinR^(#) is as defined above.

A “sulfone” group is a radical of the formula: —S(═O)₂(R^(#)), whereinR^(#) is as defined above.

A “sulfonylamino” group is a radical of the formula: —NHSO₂(R^(#)) or—N(alkyl)SO₂(R^(#)), wherein each alkyl and R^(#) are defined above.

A “sulfonamide” group is a radical of the formula: —S(═O)₂N(R^(#))₂, or—S(═O)₂NH(R^(#)), or —S(═O)₂NH₂, wherein each R^(#) is independently asdefined above.

A “phosphonate” group is a radical of the formula: —P(═O)(O(R^(#)))₂,—P(═O)(OH)₂, —OP(═O)(O(R^(#)))(R^(#)), or —OP(═O)(OH)(R^(#)), whereineach R^(#) is independently as defined above.

A “phosphine” group is a radical of the formula: —P(R^(#))₂, whereineach R^(#) is independently as defined above.

When the groups described herein, with the exception of alkyl group aresaid to be “substituted,” they may be substituted with any appropriatesubstituent or substituents. Illustrative examples of substituents arethose found in the exemplary compounds and embodiments disclosed herein,as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl;alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol;thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl;acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone;sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide;hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate;oxygen (═O); B(OH)₂, O(alkyl)aminocarbonyl; cycloalkyl, which may bemonocyclic or fused or non-fused polycyclic (e.g., cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocyclyl, which may bemonocyclic or fused or non-fused polycyclic (e.g., pyrrolidyl,piperidyl, piperazinyl, morpholinyl, or thiazinyl); monocyclic or fusedor non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl,pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl,quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl,pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl) aryloxy;aralkyloxy; heterocyclyloxy; and heterocyclyl alkoxy.

As used herein, the term “pharmaceutically acceptable salt(s)” refers toa salt prepared from a pharmaceutically acceptable non-toxic acid orbase including an inorganic acid and base and an organic acid and base.Suitable pharmaceutically acceptable base addition salts of the DNAPKinhibitors include, but are not limited to metallic salts made fromaluminum, calcium, lithium, magnesium, potassium, sodium and zinc ororganic salts made from lysine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine) and procaine. Suitable non-toxic acids include, butare not limited to, inorganic and organic acids such as acetic, alginic,anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic,glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic,lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic,succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonicacid. Specific non-toxic acids include hydrochloric, hydrobromic,phosphoric, sulfuric, and methanesulfonic acids. Examples of specificsalts thus include hydrochloride and mesylate salts. Others arewell-known in the art, see for example, Remington's PharmaceuticalSciences, 18^(th) eds., Mack Publishing, Easton Pa. (1990) or Remington:The Science and Practice of Pharmacy, 19^(th) eds., Mack Publishing,Easton Pa. (1995).

As used herein and unless otherwise indicated, the term “clathrate”means a DNAPK inhibitor, or a salt thereof, in the form of a crystallattice that contains spaces (e.g., channels) that have a guest molecule(e.g., a solvent or water) trapped within or a crystal lattice wherein aDNAPK inhibitor is a guest molecule.

As used herein and unless otherwise indicated, the term “solvate” meansa DNAPK inhibitor, or a salt thereof, that further includes astoichiometric or non-stoichiometric amount of a solvent bound bynon-covalent intermolecular forces. In one embodiment, the solvate is ahydrate.

As used herein and unless otherwise indicated, the term “hydrate” meansa DNAPK inhibitor, or a salt thereof, that further includes astoichiometric or non-stoichiometric amount of water bound bynon-covalent intermolecular forces.

As used herein and unless otherwise indicated, the term “prodrug” meansa DNAPK inhibitor derivative that can hydrolyze, oxidize, or otherwisereact under biological conditions (in vitro or in vivo) to provide anactive compound, particularly a DNAPK inhibitor. Examples of prodrugsinclude, but are not limited to, derivatives and metabolites of a DNAPKinhibitor that include biohydrolyzable moieties such as biohydrolyzableamides, biohydrolyzable esters, biohydrolyzable carbamates,biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzablephosphate analogues. In certain embodiments, prodrugs of compounds withcarboxyl functional groups are the lower alkyl esters of the carboxylicacid. The carboxylate esters are conveniently formed by esterifying anyof the carboxylic acid moieties present on the molecule. Prodrugs cantypically be prepared using well-known methods, such as those describedby Burger's Medicinal Chemistry and Drug Discovery 6^(th) ed. (Donald J.Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H.Bundgaard ed., 1985, Harwood Academic Publishers Gmfh).

As used herein and unless otherwise indicated, the term “stereoisomer”or “stereomerically pure” means one stereoisomer of a DNAPK inhibitorthat is substantially free of other stereoisomers of that compound. Forexample, a stereomerically pure compound having one chiral center willbe substantially free of the opposite enantiomer of the compound. Astereomerically pure compound having two chiral centers will besubstantially free of other diastereomers of the compound. A typicalstereomerically pure compound comprises greater than about 80% by weightof one stereoisomer of the compound and less than about 20% by weight ofother stereoisomers of the compound, greater than about 90% by weight ofone stereoisomer of the compound and less than about 10% by weight ofthe other stereoisomers of the compound, greater than about 95% byweight of one stereoisomer of the compound and less than about 5% byweight of the other stereoisomers of the compound, or greater than about97% by weight of one stereoisomer of the compound and less than about 3%by weight of the other stereoisomers of the compound. The DNAPKinhibitors can have chiral centers and can occur as racemates,individual enantiomers or diastereomers, and mixtures thereof. All suchisomeric forms are included within the embodiments disclosed herein,including mixtures thereof. The use of stereomerically pure forms ofsuch DNAPK inhibitors, as well as the use of mixtures of those forms areencompassed by the embodiments disclosed herein. For example, mixturescomprising equal or unequal amounts of the enantiomers of a particularDNAPK inhibitor may be used in methods and compositions disclosedherein. These isomers may be asymmetrically synthesized or resolvedusing standard techniques such as chiral columns or chiral resolvingagents. See, e.g., Jacques, J., et al., Enantiomers, Racemates andResolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al.,Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of CarbonCompounds (McGraw-Hill, N Y, 1962); and Wilen, S. H., Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind., 1972).

It should also be noted the DNAPK inhibitors can include E and Zisomers, or a mixture thereof, and cis and trans isomers or a mixturethereof. In certain embodiments, the DNAPK inhibitors are isolated aseither the cis or trans isomer. In other embodiments, the DNAPKinhibitors are a mixture of the cis and trans isomers.

“Tautomers” refers to isomeric forms of a compound that are inequilibrium with each other. The concentrations of the isomeric formswill depend on the environment the compound is found in and may bedifferent depending upon, for example, whether the compound is a solidor is in an organic or aqueous solution. For example, in aqueoussolution, pyrazoles may exhibit the following isomeric forms, which arereferred to as tautomers of each other:

As readily understood by one skilled in the art, a wide variety offunctional groups and other structures may exhibit tautomerism and alltautomers of the DNAPK inhibitors are within the scope of the presentinvention.

It should also be noted the DNAPK inhibitors can contain unnaturalproportions of atomic isotopes at one or more of the atoms. For example,the compounds may be radiolabeled with radioactive isotopes, such as forexample tritium (³H), iodine-125 (¹²⁵I), sulfur-35 (³⁵S), or carbon-14(¹⁴C), or may be isotopically enriched, such as with deuterium (²H),carbon-13 (¹³C), or nitrogen-15 (¹⁵N). As used herein, an “isotopologue”is an isotopically enriched compound. The term “isotopically enriched”refers to an atom having an isotopic composition other than the naturalisotopic composition of that atom. “Isotopically enriched” may alsorefer to a compound containing at least one atom having an isotopiccomposition other than the natural isotopic composition of that atom.The term “isotopic composition” refers to the amount of each isotopepresent for a given atom. Radiolabeled and isotopically enrichedcompounds are useful as therapeutic agents, e.g., cancer andinflammation therapeutic agents, research reagents, e.g., binding assayreagents, and diagnostic agents, e.g., in vivo imaging agents. Allisotopic variations of the DNAPK inhibitors as described herein, whetherradioactive or not, are intended to be encompassed within the scope ofthe embodiments provided herein. In some embodiments, there are providedisotopologues of the DNAPK inhibitors, for example, the isotopologuesare deuterium, carbon-13, or nitrogen-15 enriched DNAPK inhibitors.

“Treating” as used herein, means an alleviation, in whole or in part, ofa Wnt-associated cancer, or a symptom thereof, or slowing, or halting offurther progression or worsening of a Wnt-associated cancer.

“Preventing” as used herein, means the prevention of the onset,recurrence or spread, in whole or in part, of a Wnt-associated cancer,or a symptom thereof.

The term “effective amount” in connection with an DNAPK inhibitor meansan amount capable of alleviating, in whole or in part, symptomsassociated with a Wnt-associated cancer, or slowing or halting furtherprogression or worsening of those symptoms. The effective amount of theDNAPK inhibitor, for example in a pharmaceutical composition, may be ata level that will exercise the desired effect; for example, about 0.005mg/kg of a subject's body weight to about 100 mg/kg of a patient's bodyweight in unit dosage for both oral and parenteral administration. Aswill be apparent to those skilled in the art, it is to be expected thatthe effective amount of a DNAPK inhibitor disclosed herein may varydepending on the severity of the indication being treated.

The terms “patient” and “subject” as used herein include an animal,including, but not limited to, an animal such as a cow, monkey, horse,sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit orguinea pig, in one embodiment a mammal, in another embodiment a human.In one embodiment, a “patient” or “subject” is a human having aWnt-associated cancer.

“Wnt-associated cancer” refers to tumors in which Wnt signaling isdysregulated. This includes solid tumors (such as gastric cancer, breastcancer, endometrial cancer, uterine cancer, colorectal cancer, synovialsarcoma, pancreatic cancer, melanoma, lobular carcinoma, prostatecancer, triple negative breast cancer (TNBC), non-small cell lung cancer(NSCLC), squamous cell lung carcinoma, lung adenocarcinoma,hepatocellular cancer (HCC), ovarian cancer, adenoid carcinoma,adrenocortical carcinoma, bladder/urothelial carcinoma, glioblastomamultiforme (GBM), cervical cancer, head and neck squamous cell carcinoma(HNSCC), kidney cancer, and thyroid cancer) and hematologic malignancies(such as acute myelogenous leukemia (AML), acute lymphoblastic leukemia(ALL), multiple myeloma (MM), chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML)), as well as cancer stem cells inmany tumors types, particularly those described herein.

“Wnt-inhibitors” refers to agents which reverse the dysregulated Wntsignaling in tumors and include downstream inhibitors of beta-catenin(niclosamide, XAV939, IWR, G0070-LK, Tautomycin, Pyrvinium, HQBA,PKF115-724, PKF115-584, PKF222-815, CGP049090, PRI-724, ICG001, AV65,JW55, G244-LM, WIKI4, iCRT3, iCRT5, iCRT14, 2,3 diamino-quinazoline,BC21, PNU-74654, curcumin, quercetin, RPI724, indirubins, bis-indoles,bio, DIF, Hexachlorophene, resveratrol), inhibitors of Wnt secretion(such as ETC-159, C59, IWP, LGK974), as well as recombinant proteinsthat decrease interactions of Wnt with their receptors (anti-Wntantibodies, Foxy-5, sFRP, WIF1, anti-frizzled receptor antibodies(vantictumab), anti-RSPO3 antibodies, SOST, DKK, Fz decoy receptorfusion protein (OMP-54F28), FRZ8CRD, LRP inhibitors) or block aspects ofWnt signaling (such as NSC668036, 3289-8625, PCN-N3, FJ9, AV65,artificial F-Box, NSAIDs (such as sulindac, aspirin, celecoxib,rofecoxib, valdecoxib), thiazolidinedione antidiabetic agents(glitazones), AVI-4126, R-roscovitine (CYC202), rapamycin, or CCI-779).

“Wnt pathway modulators” include those which affect the hedgehog pathway(Smo antagonists (vismodegib, sonidegib, saridegib, BMS-833923,PF-04449913, LEQ506, TAK-441), Robotnikinin), the Notch pathways (mAbsto Notch ligands, notch decoys, mAbs to Notch receptors, g-secretaseinhibitors, mABs to nicastrin), ABC transporters, chemotherapies (suchas FOLFOX6, gemcitibine, dasatinib, cytarabine, paclitaxel, docetaxel,nab-paclitaxel, sorafenib, carboplatin or radiolabelled antibodies (suchas OTSA101 (radiolabelled anti-Frizzled-10 antibody), and those whichimpact other signaling pathways, such as inhibitors of theRas/Raf/MEK/ERK pathway, TGFb pathway, EGFR pathway (Tarceva, Iressa),PI3K/AKT/mTOR pathway, PPARγ (Troglitazone, rosiglitazone), PDGFR, KIT,Abl (STI-571, imatinib), retinoid X receptors (RXRs)/retinoic acidreceptors (RARs) (such as 9-cis-RA, 4-HPR, IIF).

“Markers of Wnt activity” as used herein include mutations, copy numbervariations (CNV's, gains or losses), fusions, decreased/increasedexpression or mislocalization of miRNA, mRNA or protein, or changes inphosphorylation or activity of Wnt pathway genes or regulators (such asfor example, Wnt ligands (including Wnt 1, 2, 2b, 3, 3a, 4, 5a, 5b, 6,7a, 7b, 8a, 8b, 9a, 9b, 10a, 10b, 11, 16), Wnt receptors Frizzled's (Fzd1, 2, 3, 4, 5, 6, 7, 8, 9, 10), LRP 5,6, APC, APC2, beta-catenin, GSK3α,GSK3β, β-TrCP, R-spondins RSPO1,2,3,4, LRP5/6, DVL1, DVL2, DVL3, EP300,FBXW11, FBXW2, FBXW4, FGF4, FOSL1, FOXN1, FRAT1, FRAT2, HDAC1, HPRT1,Jun, KREMEN1, CK1a, cmyc, GSKβ. AXIN1, AXIN2, c-myc, cyclin Dl, ACTB,AES, B2M, Bcl9, BTRC, CACYBP, CAMK2A, CAMK2B, CAMK2D, CAMK2G, CER1,CHD8, CHP2, CREBBP, CSNK1A1, CSNK1A1L, CSNK1D, CSNK1E, CSNK1G1, CSNK2A1,CSNK2A2, CSNK2B, CUL1, DAAM1, DAAM2, DIXDC1, DKK1, DKK2, DKK4, MAPK3K7,MAPK10, MAPK9, MMP7, YAP, TRIB2, HNF1A, PPARG, MMP7, CD44, COX2, LEF1,LEF2, sFRP1,2,4,5, WIF1, WIF2, Dkk-1,2,3, NKD1, Sox10, Sox17, HSulf1,RUNX3, PRDM5, RASSF10, OSR1, EZF1, HIPK1, RUNX2, PPN, DCH17, EZH2,HMGA1,2, YY1, TC1, CXXC4, TRF1, CPAP/CENP, plakoglobin, NuMA, IRAP,DACT1, DACT3, CTBP1, CTBP2, HNF4a, BTBC, CCND2, CCND3, TCF7L1, TCF7L2,TCF7, NFAT5, NFATC1, NFATC2, NFATC4, NKD2, NLK, PITX2, PLCB1, PLCB2,PLCB3, PLCB4, PORCN, PPARD, PPP2CA, PPP2CB, PPP2R1A, PPP2R1B, PPP2R5A,PPP2R5B, PPP2R5C, PPP2R5D, PPP2R5E, PPP3CA, PPP3CB, PPP3CC, PPP3R1,PPP3R2, PRICKLE1, PRICKLE2, PRKACB, PRKACG, PRKX, PSEN1, PSMA1-8,PSMB1-9, PSMC1-6, PSMD1-14, PSME1,2,4, PSMF1, PYGO1, RAC1,-3, RBX1,RHOA, RHOU, ROCK1,2, RPL13A, RPS27A, RUVBL1, SENP2, SFRP1,2,4,5, SIAH1,SKP1, SLC9A3R1, SMAD2,3,4, SOX17, T, TAB 1, TBL1, TBL1XR1, TLE1,2, TP53,UBA52, VANGL1, 2, WIF1, CTNNB1, CTNNBIP1ZNRF3, Notch1, Notch 2, Notch 3,Notch 4, Jagged 1, Jagged 2, numb, Gli1, TGFb, Sox2, Oct3/4, Klf4,Nanog, CDH1, CDH2, Zeb1, Zeb2, miR-17-92, Mir-10a, Has-miR-335,has-miR-375, miR-34c, miR-200c, miR203). Also included is the Wntsignature found via inhibition of Wnt (Ashihara, E. et al. CancerScience vol 106, no 6, 665-671)), activation of other pathways (SMAD4mutations, KRAS mutations) and markers (such as Sox7, RACK 1, ZNFR3,CDH8, PLA2GRA, Has-miR193b, miR 200a), which have been found to beassociated with increased Wnt activity and/or response to inhibition ofthe Wnt pathway.

4.2 BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides: Unbiased assessment of the prognostic potential of allkinases in the clinical cohort. The log 2 odds ratio of having ametastatic event with expression of every kinase is shown. Each kinaseis represented by a bar. The enrichment of DNAPK is shown as the veryleft-most bar (panel A); Kaplan-Meier curves of clinical outcomes(metastasis-free survival, prostate cancer specific survival, andoverall survival) by DNAPK low to high expression in discovery (cohort1, n=545) and validation (cohort 2, n=130) cohorts (panel B); andOncomine analysis of DNAPK expression in primary (left) vs metastatic(right) prostate cancer (panel C).

FIG. 2 provides: Representative images (200×) and crystal violetquantification of migration (panel A) and invasion (panel B) of C4-2,LNCaP-AR and PC3 cells in Boyden chamber assays after DNAPK knockdown(siRNA) or inhibition (NU7441); C4-2, LNCaP-AR and PC3 cell growthcurves after DNAPK inhibition (NU7441) (panel C) or knockdown (siRNA)(panel D); and DNAPK knockdown by siRNA relative to non-targeting(siNTC) control (panel E). *p<0.05, **p<0.05 compared to respectivecontrols. All graphs are mean±S.D.

FIG. 3 provides: Scatter plot of GSEA normalized enrichment scores (NES)for all pathways in the discovery clinical cohort (based on genecorrelations with DNAPK) and in vitro knockdown of DNAPK (in VCaP, C4-2,PC3, DU145 cells; y axis). The gray datapoint for the Wnt signalingpathway is above the corresponding text (panel A); Expression of Wntpathway target genes in CRPC cells LNCaP-AR and C4-2 compared tohormone-naive LNCaP cells (panel B); Growth curves of LNCaP cells undernormal serum (black) or androgen-deprivation (charcoal-stripped serum,gray) conditions (panel C); Expression of Wnt pathway target genes inLNCaP cells grown in normal serum (black), or androgen deprivation(charcoal-stripped serum) conditions with control (siNTC, light gray) orDNAPK knockdown (siDNAPK, dark gray) (panel D); and Growth curves ofandrogen deprivation-resistant LNCaP cells (charcoal-stripped serum frompanel C) switched to normal serum (black), or continued in androgendeprivation (charcoal-stripped serum) with control (siNTC, light gray)or DNAPK knockdown (siDNAPK, dark gray) (panel E). *=p<0.05, **p=<0.001.All graphs are mean±S.D. RQ=relative quantity. siNTC=non-targeting siRNAcontrol.

FIG. 4 provides: Expression of Wnt pathway genes after DNAPK knockdown(panel A) or inhibition (NU7441) (panel B) in LNCaP-AR cells; Immunoblotanalyses of DNAPK, phospho-DNAPK (pDNAPK), active beta catenin(βcatenin), and cMyc levels in LNCaP-AR and C4-2 cells after DNAPKknockdown (siDNAPK) or inhibition (NU7441) with or without Wnt3Astimulation (panels C-D); Representative images (200×) and crystalviolet quantification of LNCaP-AR and C4-2 cell invasion and migrationafter DNAPK inhibition (NU7441 or Compound 1) with or without Wnt3Astimulation (panel E); and Representative images (200×) and crystalviolet quantification of enzalutamide-resistant LNCaP-AR(LNCaP-AR-enza-res) cell invasion and migration after DNAPK inhibition(NU7441 or Compound 1) or continued enzalutamide treatment (Enza) (panelF). All graphs are mean±S.D. *=p<0.05 compared to respective controls.Enza=enzalutamide. Enza-res=enzalutamide resistant. RQ=relativequantity. siNTC=non-targeting siRNA control.

FIG. 5 provides: Immunoblot analyses of DNAPK, KU70 and LEF1 after DNAPKimmunoprecipitation (left), and LEF1 and DNAPK after LEF1immunoprecipitation (right) in LNCaP-AR cells (panel A); TOPFLASHluciferase reporter activity in PC3 cells after DNAPK inhibition(NU7441) and/or Wnt3A stimulation; activity is normalized to renillaluciferase (panel B); and Representative images (200×) and crystalviolet quantification of LNCaP-AR and C4-2 cell invasion and migrationafter DNAPK, LEF1 or beta catenin (CTNNB1) knockdown by siRNA. *=p<0.05compared to respective controls, #=p<0.05 compared to Wnt3A (panel C).All graphs are mean±S.D. siNTC=non targeting siRNA control.

FIG. 6 provides: Growth curves of LNCaP-AR xenografts in castrated micetreated daily with vehicle (black, n=5) or 25 mg/kg NU7441 (gray, n=6)(panel A); Fold change in final tumor volume (panel B); Kaplan-Meiercurves of freedom from tumor doubling time with vehicle or NU7441 (25mg/kg) treatment of LNCaP-AR xenograft tumors (panel C); Growth curvesof LNCaP-AR xenograft tumors with 5 times weekly oral gavageenzalutamide (10 mg/kg, n=16), Compound 1 (2 mg/kg, n=14), Compound1+enzalutamide (n=14), or vehicle (n=14) treatment. Bar graph representschange in final tumor volume compared to starting tumor volume (panelD); Kaplan-Meier curves of freedom from tumor tripling withenzalutamide, Compound 1, enzalutamide+Compound 1, or vehicle treatmentof LNCaP-AR xenograft tumors (panel E); Expression of select Wnt pathwaytarget genes in human primary prostate tumor explants treated withNU7441 (n=6) or vehicle (panel F); and Representative images of Ki67immunostaining of human primary prostate tumor explants treated withNU7441 (n=6) or vehicle; Ki67-positive nuclei are indicated with arrows(panel G). All graphs are mean±S.E.M. *=p<0.05 compared to respectivecontrol, #=p<0.05 for enzalutamide compared to Compound 1+enzalutamide,**=p<0.01 for Compound 1 compared to vehicle.

FIG. 7 provides: Scatter plot showing correlation between DNAPK and 3catenin (CTNNB1) expression in the discovery cohort (Clinical Cohort 1,n=545) (panel A); and Expression of Wnt pathway target genes inAR-independent PC3 cells relative to androgen-sensitive LNCaP cells(panel B). GAPDH was used as internal reference, bars are mean±S.D.RQ=relative quantity.

FIG. 8 provides: Expression of Wnt pathway genes in C4-2 cells afterinhibition (NU7441) (panel A) or knockdown (panel B) of DNAPK; andExpression of Notch pathway genes in LNCaP-AR, PC3 and C4-2 cells afterknockdown of DNAPK (panel C). GAPDH was used as internal reference, barsare mean±S.D. *=p<0.05. RQ=relative quantity.

FIG. 9 provides: Expression of Wnt pathway target genes in LNCaP-ARcells grown in enzalutamide until resistance (LNCaP-AR-enza-res)relative to LNCaP-AR cells grown in vehicle (DMSO) (panel A); andExpression of AR or AR-target genes FKBP5 and KLK3 (PSA) inLNCaP-AR-enza-res cells after treatment with 10 μM enzalutamide (panelB). GAPDH was used as internal reference, bars are mean±S.D. *=p<0.05.RQ=relative quantity.

FIG. 10 provides: Body weight measurements of LNCaP-AR xenograft miceafter treatment with NU7441 (panel A); Growth curves of VCaP xenografttumors with various doses of Compound 1 (administered once daily viaoral gavage, 5 times per week for 6 weeks) or vehicle (panel B); Bodyweight measurements of VCaP xenograft mice after treatment with variousCompound 1 doses (panel C); and Growth curves of PC3 xenograft tumorstreated with Compound 1 or vehicle (panel D). All graphs are mean±S.E.M.*=p<0.05 compared to vehicle.

4.3 DNAPK INHIBITORS

The compounds provided herein are generally referred to as “DNAPKinhibitor(s).”

In one embodiment, the DNAPK inhibitors include compounds having thefollowing formula (I):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, metabolites, isotopologues and prodrugsthereof, wherein:

R¹ is substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted aryl, substituted or unsubstituted cycloalkyl, substitutedor unsubstituted heterocyclyl, or substituted or unsubstitutedheterocyclylalkyl;

R² is H, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted heterocyclylalkyl, substituted orunsubstituted aralkyl, or substituted or unsubstituted cycloalkylalkyl;

R³ is H, or a substituted or unsubstituted C₁₋₈ alkyl,

wherein in certain embodiments, the DNAPK inhibitors do not include7-(4-hydroxyphenyl)-1-(3-methoxybenzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one,depicted below:

In some embodiments of compounds of formula (I), R¹ is substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl. Forexample, R¹ is phenyl, pyridyl, pyrimidyl, benzimidazolyl,1H-pyrrolo[2,3-b]pyridyl, indazolyl, indolyl, 1H-imidazo[4,5-b]pyridyl,1H-imidazo[4,5-b]pyridin-2(3H)-onyl, 3H-imidazo[4,5-b]pyridyl, orpyrazolyl, each optionally substituted. In some embodiments, R¹ isphenyl substituted with one or more substituents independently selectedfrom the group consisting of substituted or unsubstituted C₁₋₈ alkyl(for example, methyl), substituted or unsubstituted heterocyclyl (forexample, a substituted or unsubstituted triazolyl or pyrazolyl),aminocarbonyl, halogen (for example, fluorine), cyano, hydroxyalkyl andhydroxy. In other embodiments, R¹ is pyridyl substituted with one ormore substituents independently selected from the group consisting ofsubstituted or unsubstituted C₁₋₈ alkyl (for example, methyl),substituted or unsubstituted heterocyclyl (for example, a substituted orunsubstituted triazolyl), halogen, aminocarbonyl, cyano, hydroxyalkyl(for example, hydroxypropyl), —OR, and —NR₂, wherein each R isindependently H, or a substituted or unsubstituted C₁₋₄ alkyl. In someembodiments, R¹ is 1H-pyrrolo[2,3-b]pyridyl or benzimidazolyl,optionally substituted with one or more substituents independentlyselected from the group consisting of substituted or unsubstituted C₁₋₈alkyl, and —NR₂, wherein R is independently H, or a substituted orunsubstituted C₁₋₄ alkyl.

In some embodiments, R¹ is

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₄ alkyl (for example, methyl); R′ is at each occurrenceindependently a substituted or unsubstituted C₁₋₄ alkyl (for example,methyl), halogen (for example, fluoro), cyano, —OR, or —NR₂; m is 0-3;and n is 0-3. It will be understood by those skilled in the art that anyof the substituents R′ may be attached to any suitable atom of any ofthe rings in the fused ring systems.

In some embodiments of compounds of formula (I), R¹ is

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₄ alkyl; R′ is at each occurrence independently asubstituted or unsubstituted C₁₋₄ alkyl, halogen, cyano, —OR or —NR₂; mis 0-3; and n is 0-3.

In some embodiments of compounds of formula (I), R² is H, substituted orunsubstituted C₁₋₈ alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedC₁₋₄ alkyl-heterocyclyl, substituted or unsubstituted C₁₋₄ alkyl-aryl,or substituted or unsubstituted C₁₋₄ alkyl-cycloalkyl. For example, R²is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,tert-butyl, n-pentyl, isopentyl, cyclopentyl, cyclohexyl,tetrahydrofuranyl, tetrahydropyranyl, (C₁₋₄ alkyl)-phenyl, (C₁₋₄alkyl)-cyclopropyl, (C₁₋₄ alkyl)-cyclobutyl, (C₁₋₄ alkyl)-cyclopentyl,(C₁₋₄ alkyl)-cyclohexyl, (C₁₋₄ alkyl)-pyrrolidyl, (C₁₋₄alkyl)-piperidyl, (C₁₋₄ alkyl)-piperazinyl, (C₁₋₄ alkyl)-morpholinyl,(C₁₋₄ alkyl)-tetrahydrofuranyl, or (C₁₋₄ alkyl)-tetrahydropyranyl, eachoptionally substituted.

In other embodiments, R² is H, C₁₋₄ alkyl, (C₁₋₄alkyl)(OR),

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₄ alkyl (for example, methyl); R′ is at each occurrenceindependently H, —OR, cyano, or a substituted or unsubstituted C₁₋₄alkyl (for example, methyl); and p is 0-3.

In other embodiments of compounds of formula (I), R² is H, C₁₋₄ alkyl,(C₁₋₄alkyl)(OR),

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₂ alkyl; R′ is at each occurrence independently H, —OR,cyano, or a substituted or unsubstituted C₁₋₂ alkyl; and p is 0-1.

In other embodiments of compounds of formula (I), R³ is H.

In some such embodiments described herein, R¹ is substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. Forexample, R¹ is phenyl, pyridyl, pyrimidyl, benzimidazolyl,1H-pyrrolo[2,3-b]pyridyl, indazolyl, indolyl, 1H-imidazo[4,5-b]pyridine,pyridyl, 1H-imidazo[4,5-b]pyridin-2(3H)-onyl, 3H-imidazo[4,5-b]pyridyl,or pyrazolyl, each optionally substituted. In some embodiments, R¹ isphenyl substituted with one or more substituents independently selectedfrom the group consisting of substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted heterocyclyl, aminocarbonyl, halogen,cyano, hydroxyalkyl and hydroxy. In others, R¹ is pyridyl substitutedwith one or more substituents independently selected from the groupconsisting of C₁₋₈ alkyl, substituted or unsubstituted heterocyclyl,halogen, aminocarbonyl, cyano, hydroxyalkyl, —OR, and —NR₂, wherein eachR is independently H, or a substituted or unsubstituted C₁₋₄ alkyl. Instill others, R¹ is 1H-pyrrolo[2,3-b]pyridyl or benzimidazolyl,optionally substituted with one or more substituents independentlyselected from the group consisting of substituted or unsubstituted C₁₋₈alkyl, and —NR₂, wherein R is independently H, or a substituted orunsubstituted C₁₋₄ alkyl.

In certain embodiments, the compounds of formula (I) have an R¹ groupset forth herein and an R² group set forth herein.

In some embodiments of compounds of formula (I), the compound inhibitsDNAPK.

In some embodiments of compounds of formula (I), the compound at aconcentration of 10 μM inhibits DNAPK by at least about 50%. Compoundsof formula (I) may be shown to be inhibitors of DNAPK in any suitableassay system.

Representative DNAPK inhibitors of formula (I) include compounds fromTable A.

TABLE A7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(cis-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((cis-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-ethyl-7-(1H-pyrrolo[3,2-b]pyridin-5-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((cis-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-benzo[d]imidazol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((trans-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(cis-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(cis-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-bl]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-ethyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((cis-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-indol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((trans-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((cis-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(trans-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(trans-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-ethyl-7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-hydroxypyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-isopropyl-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;5-(8-isopropyl-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide;7-(1H-indazol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-aminopyrimidin-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-aminopyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(methylamino)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-hydroxypyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(4-(1H-pyrazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-indazol-4-yl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-indazol-6-yl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(pyrimidin-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-methoxypyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(2-methoxyethyl)-7-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-ethyl-7-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-ethyl-7-(1H-indazol-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(pyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-aminopyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;l-methyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;2-(2-hydroxypropan-2-yl)-5-(8-(trans-4-methoxycyclohexyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)pyridine 1-oxide;4-methyl-5-(7-oxo-8-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)picolinamide;5-(8-((cis-4-methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide;7-(1H-pyrazol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(trans-4-methoxycyclohexyl)-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;3-((7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-2-oxo-3,4-dihydropyrazino[2,3-b]pyrazin-1(2H)-yl)methyl)benzonitrile;1-((trans-4-methoxycyclohexyl)methyl)-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;3-(7-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)benzamide;5-(8-((trans-4-methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide;3-((7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-oxo-3,4-dihydropyrazino[2,3-b]pyrazin-1(2H)-yl)methyl)benzonitrile;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1R,3R)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1S,3R)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1S,3S)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1R,3S)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-indazol-6-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-morpholinoethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(trans-4-hydroxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(cis-4-hydroxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-morpholinoethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-isopropyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-imidazo[4,5-b]pyridin-6-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-((cis-4-methoxycyclohexyl)methyl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(trans-4-hydroxycyclohexyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(cis-4-hydroxycyclohexyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;4-(7-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)benzamide;7-(1H-indazol-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-((1S,3R)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-((1R,3R)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-((1R,3S)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-((1S,3S)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-indol-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-indol-6-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(4-(2-hydroxypropan-2-yl)phenyl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-((trans-4-methoxycyclohexyl)methyl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((cis-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(2-methoxyethyl)-7-(4-methyl-2-(methylamino)-1H-benzo[d]imidazol-6-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(7-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(2-methoxyethyl)-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;l-benzyl-7-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(3-fluoro-4-(4H-1,2,4-triazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(3-fluoro-4-(4H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(3-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(trans-4-methoxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(trans-4-rnethoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(3-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(2-methoxyethyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(cyclopentylmethyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(4-(2-hydroxypropan-2-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;(S)-7-(6-(1-hydroxyethyl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;(R)-7-(6-(1-hydroxyethyl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(4-(2-hydroxypropan-2-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(4-(trifluoromethyl)benzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(3-(trifluoromethyl)benzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(3-methoxypropyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(4-methyl-2-(methylamino)-1H-benzo[d]imidazol-6-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-amino-4-methyl-1H-benzo[d]imidazol-6-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;(R)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-methyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;(S)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-methyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,3-dimethyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-amino-4-methyl-1H-benzo[d]imidazol-6-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(4-(1H-1,2,4-triazol-5-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(1-hydroxypropan-2-yl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; and1-(2-hydroxyethyl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, and pharmaceutically acceptablesalts, clathrates, solvates, stereoisomers, tautomers, metabolites,isotopologues and prodrugs thereof.

In one embodiment, Compound 1 is1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one,or a tautomer thereof, for example,1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one,or1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one.

4.4 Methods for Making DNAPK Inhibitors

The DNAPK inhibitors can be obtained via standard, well-known syntheticmethodology, see e.g., March, J. Advanced Organic Chemistry; ReactionsMechanisms, and Structure, 4th ed., 1992. Starting materials useful forpreparing compounds of formula (III) and intermediates therefore, arecommercially available or can be prepared from commercially availablematerials using known synthetic methods and reagents.

Particular methods for preparing compounds of formula (I) are disclosedin U.S. Pat. No. 8,110,578, issued Feb. 7, 2012, and U.S. Pat. No.8,569,494, issued Oct. 29, 2013, each incorporated by reference hereinin their entirety.

4.5 Methods of Use

Provided herein are methods for treating or preventing Wnt-associatedcancers, comprising administering an effective amount of a DNAPKinhibitor to a patient having a Wnt-associated cancer as well as the useof a DNAPK-inhibitor in methods for treating or preventingWnt-associated cancers.

Further provided herein are methods for inhibiting or preventingmetastasis of Wnt-associated cancers, comprising administering aneffective amount of a DNAPK inhibitor to a patient having aWnt-associated cancer.

Further provided herein are methods for inhibiting or preventingexpansion or survival of cancer stem cells of Wnt-associated cancers,comprising contacting the cancer stem cells of a Wnt-associated cancerwith an effective amount of a DNAPK inhibitor. In certain embodiments,the contacting of a cancer stem cell of a Wnt-associated cancer with aneffective amount of a DNAPK inhibitor is achieved by administering aDNAPK inhibitor to a patient having a Wnt-associated cancer. In otherembodiments, the contacting of a cancer stem cell of a Wnt-associatedcancer with an effective amount of a DNAPK inhibitor is achieved bycontacting a biological sample (e.g., a tumor, blood or tissue sample)of a patient having a Wnt-associated cancer ex vivo with a DNAPKinhibitor.

Further provided herein are methods for inhibiting or preventingexpansion or survival of resistant and/or refractory tumor cells ofWnt-associated cancers, comprising contacting the tumor cells of theWnt-associated cancer with an effective amount of a DNAPK inhibitor. Incertain embodiments, the contacting of a resistant and/or refractorytumor cell of a Wnt-associated cancer with an effective amount of aDNAPK inhibitor is achieved by administering a DNAPK inhibitor to apatient having a resistant and/or refractory Wnt-associated cancer. Inother embodiments, the contacting of a resistant and/or refractory tumorcell of Wnt-associated cancer with an effective amount of a DNAPKinhibitor is achieved by contacting a biological sample (e.g., a tumor,blood or tissue sample) of a patient having a resistant and/orrefractory Wnt-associated cancer ex vivo with a DNAPK inhibitor.

Wnt-associated cancers include, but are not limited to, solid tumors(such as gastric cancer, breast cancer, endometrial cancer, uterinecancer, colorectal cancer, synovial sarcoma, pancreatic cancer,melanoma, lobular carcinoma, prostate cancer, triple negative breastcancer (TNBC), non-small cell lung cancer (NSCLC), squamous cell lungcarcinoma, lung adenocarcinoma, hepatocellular cancer (HCC), ovariancancer, adenoid carcinoma, adrenocortical carcinoma, bladder/urothelialcarcinoma, glioblastoma multiforme (GBM), cervical cancer, head and necksquamous cell carcinoma (HNSCC), kidney cancer, and thyroid cancer) andhematologic malignancies (such as acute myelogenous leukemia (AML),acute lymphoblastic leukemia (ALL), multiple myeloma (MM), chroniclymphocytic leukemia (CLL), chronic myelogenous leukemia (CML)), as wellas cancer stem cells in many tumors types, particularly those describedherein. In one embodiment, the Wnt-associated cancer is castrationresistant prostate cancer.

Further provided herein are methods for treating or preventing androgendeprivation therapy-resistant cancers, comprising administering aneffective amount of a DNAPK inhibitor to a patient having an androgendeprivation therapy-resistant cancer. In some embodiments, the methodadditionally comprises administering and effective amount of a Wntpathway modulator, a Wnt inhibitor, and/or an androgen receptor (AR)antagonist.

Androgen deprivation therapy-resistant cancers include, but are notlimited to, castration-resistant prostate cancer and AR positive tumors,such as breast cancer, cervical cancer, endometrial cancer, livercancer, melanoma, ovarian cancer, renal cancer, skin cancer, testicularcancer, and urothelial cancer(http://www.proteinatlas.org/ENSG00000169083-AR/cancer). In oneembodiment, the AR antagonist is Enzalutamide.

Further provided herein are methods for preventing androgen deprivationtherapy resistance in cancers, comprising administering an effectiveamount of a DNAPK inhibitor to a patient having cancer. In someembodiment, the cancer is prostate cancer, breast cancer, cervicalcancer, endometrial cancer, liver cancer, melanoma, ovarian cancer,renal cancer, skin cancer, testicular cancer, or urothelial cancer. Insome embodiments, the method additionally comprises administering andeffective amount of a Wnt pathway modulator as described herein and/oran androgen receptor (AR) antagonist.

Further provided herein are methods for treating or preventingenzalutamide-resistant cancers, comprising administering an effectiveamount of a DNAPK inhibitor to a patient having anenzalutamide-resistant cancer. In some embodiments, the methodadditionally comprises administering and effective amount of an androgenreceptor (AR) antagonist.

Enzalutamide-resistant cancers include, but are not limited to,castration-resistant prostate cancer and AR positive tumors, such asbreast cancer, cervical cancer, endometrial cancer, liver cancer,melanoma, ovarian cancer, renal cancer, skin cancer, testicular cancer,and urothelial cancer(http://www.proteinatlas.org/ENSG00000169083-AR/cancer).

Further provided herein are methods for detecting or measuring theinhibition of DNAPK activity in a patient, comprising measuringdecreased phosphorylation of a DNAPK substrate (such as DNAPK or Hsp90a)in a biological sample from said patient, for example a peripheral bloodor tumor sample, prior to and after the administration of a DNAPKinhibitor to said patient.

Further provided herein are methods for detecting or measuring theeffect of inhibition of DNAPK activity on markers of Wnt activity in apatient, comprising measuring the markers of Wnt activity, as describedherein, in a biological sample from said patient, for example aperipheral blood or tumor sample, prior to and after the administrationof a DNAPK inhibitor to said patient, wherein modulation of markers ofWnt activity in a biological sample from said patient afteradministration of said DNAPK inhibitor relative to the markers of Wntactivity in a biological sample from said patient prior toadministration of said DNAPK inhibitor indicates inhibition of DNAPKactivity. In one embodiment, the marker of Wnt activity is one or moreof CCND1, TCF7, Wnt1, FZD5, FZD1, TCF7L2, FZD6, AXIN1, FZD4, LEF1,CTBP1, LRP5, FZD8, WIF1, WNT7B, WNT3A, CD44, HNF4A, BTRC, LRP6, CTNNB1,WNT7A, WNT16, WNT8A, WNT3, WNT6, WNT4, WNT10A, CCND2, FZD9, AXIN2,TCF7L1, APC, cMYC, WNT2B, FZD3, or NFAT5. In another embodiment, themarker of Wnt activity is one or more of DNAPK, Axin2, FZD6, LEF1, FZD4,FZD8, CCND2, CCND1, cMYC, CTNNB1, Axin1, Wnt4, FZD9, Wnt16, Wnt6, LRP6,CTBP1, CD44, FZD3, Wnt2B, TCF7L2, Wnt7A, TCF7, Wnt2, Wnt3, Wnt3A, LRP5,APC, Wnt8A, or Wnt1. In another embodiment, the marker of Wnt activityis one or more of DNAPKFZD6, LRP5, LRP6, APC, FZD8, Wnt4, Wnt3A, BTRC,FZD3, CD44cMYC, Wnt10A, CTNNB1, CTBP1, Wnt2B, TCF7L2, FZD9, CCND1Axin1,Wnt3, FZD5, Axin2, Wnt1, TCF7L1, TCF7, LEF1, FZD1, Wnt8A, or CCND2.

Also provided herein are methods for predicting the likelihood of acancer of a patient being responsive to DNAPK inhibitor therapy,comprising screening a biological sample of said patient for markers ofWnt activity, wherein the presence of markers of Wnt activity in abiological sample of said patient indicates an increased likelihood thata cancer of said patient will be responsive to DNAPK inhibitor therapy.In one embodiment, the marker of Wnt activity is one or more of CCND1,TCF7, Wnt1, FZD5, FZD1, TCF7L2, FZD6, AXIN1, FZD4, LEF1, CTBP1, LRP5,FZD8, WIF1, WNT7B, WNT3A, CD44, HNF4A, BTRC, LRP6, CTNNB1, WNT7A, WNT16,WNT8A, WNT3, WNT6, WNT4, WNT10A, CCND2, FZD9, AXIN2, TCF7L1, APC, cMYC,WNT2B, FZD3, or NFAT5. In another embodiment, the marker of Wnt activityis one or more of DNAPK, Axin2, FZD6, LEF1, FZD4, FZD8, CCND2, CCND1,cMYC, CTNNB1, Axin1, Wnt4, FZD9, Wnt16, Wnt6, LRP6, CTBP1, CD44, FZD3,Wnt2B, TCF7L2, Wnt7A, TCF7, Wnt2, Wnt3, Wnt3A, LRP5, APC, Wnt8A, orWnt1. In another embodiment, the marker of Wnt activity is one or moreof DNAPK, FZD6, LRP5, LRP6, APC, FZD8, Wnt4, Wnt3A, BTRC, FZD3,CD44cMYC, Wnt10A, CTNNB1, CTBP1, Wnt2B, TCF7L2, FZD9, CCND1Axin1, Wnt3,FZD5, Axin2, Wnt1, TCF7L1, TCF7, LEF1, FZD1, Wnt8A, or CCND2.

Further provided herein are methods for determining whether a patient issensitive to a DNAPK inhibitor, comprising administering to said patientsaid DNAPK inhibitor and determining whether markers of Wnt activity aremodulated in said patient by measuring the markers of Wnt activity in abiological sample from said patient, for example a peripheral blood ortumor sample, prior to and after the administration of the DNAPKinhibitor to said patient, wherein changes in markers of Wnt activity bysaid DNAPK inhibitor indicates that a patient is sensitive to said DNAPKinhibitor. In one embodiment, the marker of Wnt activity is one or moreof CCND1, TCF7, Wnt1, FZD5, FZD1, TCF7L2, FZD6, AXIN1, FZD4, LEF1,CTBP1, LRP5, FZD8, WIF1, WNT7B, WNT3A, CD44, HNF4A, BTRC, LRP6, CTNNB1,WNT7A, WNT16, WNT8A, WNT3, WNT6, WNT4, WNT10A, CCND2, FZD9, AXIN2,TCF7L1, APC, cMYC, WNT2B, FZD3, or NFAT5. In another embodiment, themarker of Wnt activity is one or more of DNAPK, Axin2, FZD6, LEF1, FZD4,FZD8, CCND2, CCND1, cMYC, CTNNB1, Axin1, Wnt4, FZD9, Wnt16, Wnt6, LRP6,CTBP1, CD44, FZD3, Wnt2B, TCF7L2, Wnt7A, TCF7, Wnt2, Wnt3, Wnt3A, LRP5,APC, Wnt8A, or Wnt1. In another embodiment, the marker of Wnt activityis one or more of DNAPK, FZD6, LRP5, LRP6, APC, FZD8, Wnt4, Wnt3A, BTRC,FZD3, CD44cMYC, Wnt10A, CTNNB1, CTBP1, Wnt2B, TCF7L2, FZD9, CCND1Axin1,Wnt3, FZD5, Axin2, Wnt1, TCF7L1, TCF7, LEF1, FZD1, Wnt8A, or CCND2.

Also provided herein is a kit for detecting markers of Wnt activity in abiological sample from a patient before and after treatment with a DNAPKinhibitor, comprising reagents for measuring markers of Wnt activity andone or more DNAPK markers. In one embodiment, the marker of Wnt activityis one or more of CCND1, TCF7, Wnt1, FZD5, FZD1, TCF7L2, FZD6, AXIN1,FZD4, LEF1, CTBP1, LRP5, FZD8, WIF1, WNT7B, WNT3A, CD44, HNF4A, BTRC,LRP6, CTNNB1, WNT7A, WNT16, WNT8A, WNT3, WNT6, WNT4, WNT10A, CCND2,FZD9, AXIN2, TCF7L1, APC, cMYC, WNT2B, FZD3, or NFAT5. In anotherembodiment, the marker of Wnt activity is one or more of DNAPK, Axin2,FZD6, LEF1, FZD4, FZD8, CCND2, CCND1, cMYC, CTNNB1, Axin1, Wnt4, FZD9,Wnt16, Wnt6, LRP6, CTBP1, CD44, FZD3, Wnt2B, TCF7L2, Wnt7A, TCF7, Wnt2,Wnt3, Wnt3A, LRP5, APC, Wnt8A, or Wnt1. In another embodiment, themarker of Wnt activity is one or more of DNAPK. FZD6, LRP5, LRP6, APC,FZD8, Wnt4, Wnt3A, BTRC, FZD3, CD44cMYC, Wnt10A, CTNNB1, CTBP1, Wnt2B,TCF7L2, FZD9, CCND1Axin1, Wnt3, FZD5, Axin2, Wnt1, TCF7L1, TCF7, LEF1,FZD1, Wnt8A, or CCND2.

Methods for identifying Wnt-associated cancers are known in the art(see, e.g., Tumova, L et al. Mol Cancer Ther April 2014 13:812-822;Takebe et al. Nat Rev Clin Oncol. 2015 Apr. 7. doi:10.1038/nrclinonc.2015.61. (Epub ahead of print); Madan N S and Virshup,Mol Cancer Ther. 2015 May; 14(5):1087-1094. Chiurillo, Mass. World J ExpMed. 2015 May 20; 5(2):84-102; Ashihara, E et al. Cancer Sci. 2015 June;106(6):665-71. Illustrative methods to evaluate markers of Wnt activity(mutations, copy number variations (CNV's, gains or losses), fusions,decreased/increased expression (see FIG. 3) or mislocalization of miRNA,mRNA or protein, or changes in phosphorylation or activity of Wntpathway genes or regulators) include, but are not limited to sequencing,PCR, FISH, microarrays, RT-PCR, immunohistochemistry (IHC), westernblots, ELISAs.

In some embodiments, the DNAPK inhibitor is a compound as describedherein. In one embodiment, the DNAPK inhibitor is Compound 1 (a DNAPKinhibitor set forth herein having molecular formula C₁₆H₁₆N₈O). In oneembodiment, Compound 1 is1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one,or a tautomer thereof, for example,1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one,or1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one.

A DNAPK inhibitor can be combined with radiation therapy or surgery. Incertain embodiments, a DNAPK inhibitor is administered to patient who isundergoing radiation therapy, has previously undergone radiation therapyor will be undergoing radiation therapy. In certain embodiments, a DNAPKinhibitor is administered to a patient who has undergone tumor removalsurgery. In some embodiments of the methods described herein, themethods additionally comprise administration of a Wnt pathway modulator,a Wnt inhibitor and/or an androgen receptor antagonist, as describedherein. In certain embodiments, a DNAPK inhibitor can be administeredbefore, after or simultaneously with a Wnt pathway modulator or a Wntinhibitor in the methods provided herein. A DNAPK inhibitor can also becombined with an AR antagonist such as enzalutamide in the methodsprovided herein. In certain embodiments, a DNAPK inhibitor can beadministered before, after or simultaneously with an AR antagonist suchas enzalutamide in the methods provided herein.

4.6 Pharmaceutical Compositions and Routes of Administration

Provided herein are compositions, comprising an effective amount of aDNAPK inhibitor, and compositions comprising an effective amount of aDNAPK inhibitor and a pharmaceutically acceptable carrier or vehicle. Insome embodiments, the pharmaceutical compositions described herein aresuitable for oral, parenteral, mucosal, transdermal or topicaladministration.

The DNAPK inhibitors can be administered to a patient orally orparenterally in the conventional form of preparations, such as capsules,microcapsules, tablets, granules, powder, troches, pills, suppositories,injections, suspensions and syrups. Suitable formulations can beprepared by methods commonly employed using conventional, organic orinorganic additives, such as an excipient (e.g., sucrose, starch,mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphateor calcium carbonate), a binder (e.g., cellulose, methylcellulose,hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone,gelatin, gum arabic, polyethyleneglycol, sucrose or starch), adisintegrator (e.g., starch, carboxymethylcellulose, hydroxypropylstarch, low substituted hydroxypropylcellulose, sodium bicarbonate,calcium phosphate or calcium citrate), a lubricant (e.g., magnesiumstearate, light anhydrous silicic acid, talc or sodium lauryl sulfate),a flavoring agent (e.g., citric acid, menthol, glycine or orangepowder), a preservative (e.g, sodium benzoate, sodium bisulfite,methylparaben or propylparaben), a stabilizer (e.g., citric acid, sodiumcitrate or acetic acid), a suspending agent (e.g., methylcellulose,polyvinyl pyrroliclone or aluminum stearate), a dispersing agent (e.g.,hydroxypropylmethylcellulose), a diluent (e.g., water), and base wax(e.g., cocoa butter, white petrolatum or polyethylene glycol). Theeffective amount of the DNAPK inhibitor in the pharmaceuticalcomposition may be at a level that will exercise the desired effect; forexample, about 0.005 mg/kg of a patient's body weight to about 10 mg/kgof a patient's body weight in unit dosage for both oral and parenteraladministration.

The dose of a DNAPK inhibitor to be administered to a patient is ratherwidely variable and can be subject to the judgment of a health-carepractitioner. In general, the DNAPK inhibitors can be administered oneto four times a day in a dose of about 0.005 mg/kg of a patient's bodyweight to about 10 mg/kg of a patient's body weight in a patient, butthe above dosage may be properly varied depending on the age, bodyweight and medical condition of the patient and the type ofadministration. In one embodiment, the dose is about 0.01 mg/kg of apatient's body weight to about 5 mg/kg of a patient's body weight, about0.05 mg/kg of a patient's body weight to about 1 mg/kg of a patient'sbody weight, about 0.1 mg/kg of a patient's body weight to about 0.75mg/kg of a patient's body weight, about 0.25 mg/kg of a patient's bodyweight to about 0.5 mg/kg of a patient's body weight, or about 0.007mg/kg of a patient's body weight to about 1.7 mg/kg of patient's bodyweight. In one embodiment, one dose is given per day. In anotherembodiment, two doses are given per day. In any given case, the amountof the DNAPK inhibitor administered will depend on such factors as thesolubility of the active component, the formulation used and the routeof administration.

In another embodiment, provided herein are methods for the treatment orprevention of a DNAPK and Wnt-associated cancer, comprising theadministration of about 0.375 mg/day to about 750 mg/day, about 0.75mg/day to about 375 mg/day, about 3.75 mg/day to about 75 mg/day, about7.5 mg/day to about 55 mg/day, about 18 mg/day to about 37 mg/day, about0.5 mg/day to about 60 mg/day, or about 0.5 mg/day to about 128 mg/dayof a DNAPK inhibitor to a patient in need thereof. In anotherembodiment, provided herein are methods for the treatment or preventionof a DNAPK and Wnt-associated cancer, comprising the administration ofabout 0.5 mg/day to about 1200 mg/day, about 10 mg/day to about 1200mg/day, about 100 mg/day to about 1200 mg/day, about 400 mg/day to about1200 mg/day, about 600 mg/day to about 1200 mg/day, about 400 mg/day toabout 800 mg/day or about 600 mg/day to about 800 mg/day of a DNAPKinhibitor to a patient in need thereof. In a particular embodiment, themethods disclosed herein comprise the administration of 0.5 mg/day, 1mg/day, 2 mg/day, 4 mg/day, 8 mg/day, 16 mg/day, 20 mg/day, 25 mg/day,30 mg/day, 45 mg/day, 60 mg/day, 90 mg/day, 120 mg/day or 128 mg/day ofa DNAPK inhibitor to a patient in need thereof.

In another embodiment, provided herein are unit dosage formulations thatcomprise between about 0.1 mg and about 2000 mg, about 1 mg and 200 mg,about 35 mg and about 1400 mg, about 125 mg and about 1000 mg, about 250mg and about 1000 mg, or about 500 mg and about 1000 mg of a DNAPKinhibitor.

In a particular embodiment, provided herein are unit dosage formulationcomprising about 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 5 mg, 7.5 mg, 10 mg, 15mg, 20 mg, 30 mg, 45 mg, 50 mg, 60 mg, 75 mg, 100 mg, 125 mg, 150 mg,200 mg, 250 mg, 300 mg, 400 mg, 600 mg or 800 mg of a DNAPK inhibitor.

In another embodiment, provided herein are unit dosage formulations thatcomprise 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg,200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mgor 1400 mg of a DNAPK inhibitor. In a particular embodiment, providedherein are unit dosage formulations that comprise 5 mg, 7.5 mg, 10 mg,15 mg, 20 mg, 30 mg, 45 mg or 60 mg of a DNAPK inhibitor.

A DNAPK inhibitor can be administered once, twice, three, four or moretimes daily.

A DNAPK inhibitor can be administered orally for reasons of convenience.In one embodiment, when administered orally, a DNAPK inhibitor isadministered with a meal and water. In another embodiment, the DNAPKinhibitor is dispersed in water or juice (e.g., apple juice or orangejuice) and administered orally as a suspension. In another embodiment,when administered orally, a DNAPK inhibitor is administered in a fastedstate.

The DNAPK inhibitor can also be administered intradermally,intramuscularly, intraperitoneally, percutaneously, intravenously,subcutaneously, intranasally, epidurally, sublingually, intracerebrally,intravaginally, transdermally, rectally, mucosally, by inhalation, ortopically to the ears, nose, eyes, or skin. The mode of administrationis left to the discretion of the health-care practitioner, and candepend in-part upon the site of the medical condition.

In one embodiment, provided herein are capsules containing a DNAPKinhibitor without an additional carrier, excipient or vehicle.

In another embodiment, provided herein are compositions, comprising aneffective amount of a DNAPK inhibitor and a pharmaceutically acceptablecarrier or vehicle, wherein a pharmaceutically acceptable carrier orvehicle can comprise an excipient, diluent, or a mixture thereof. In oneembodiment, the composition is a pharmaceutical composition.

The compositions can be in the form of tablets, chewable tablets,capsules, solutions, parenteral solutions, troches, suppositories andsuspensions and the like. Compositions can be formulated to contain adaily dose, or a convenient fraction of a daily dose, in a dosage unit,which may be a single tablet or capsule or convenient volume of aliquid. In one embodiment, the solutions are prepared from water-solublesalts, such as the hydrochloride salt. In general, all of thecompositions are prepared according to known methods in pharmaceuticalchemistry. Capsules can be prepared by mixing a DNAPK inhibitor with asuitable carrier or diluent and filling the proper amount of the mixturein capsules. The usual carriers and diluents include, but are notlimited to, inert powdered substances such as starch of many differentkinds, powdered cellulose, especially crystalline and microcrystallinecellulose, sugars such as fructose, mannitol and sucrose, grain floursand similar edible powders.

Tablets can be prepared by direct compression, by wet granulation, or bydry granulation. Their formulations usually incorporate diluents,binders, lubricants and disintegrators as well as the compound. Typicaldiluents include, for example, various types of starch, lactose,mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such assodium chloride and powdered sugar. Powdered cellulose derivatives arealso useful. In one embodiment, the pharmaceutical composition islactose-free. Typical tablet binders are substances such as starch,gelatin and sugars such as lactose, fructose, glucose and the like.Natural and synthetic gums are also convenient, including acacia,alginates, methylcellulose, polyvinylpyrrolidine and the like.Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

A lubricant might be necessary in a tablet formulation to prevent thetablet and punches from sticking in the die. The lubricant can be chosenfrom such slippery solids as talc, magnesium and calcium stearate,stearic acid and hydrogenated vegetable oils. Tablet disintegrators aresubstances that swell when wetted to break up the tablet and release thecompound. They include starches, clays, celluloses, algins and gums.More particularly, corn and potato starches, methylcellulose, agar,bentonite, wood cellulose, powdered natural sponge, cation-exchangeresins, alginic acid, guar gum, citrus pulp and carboxymethyl cellulose,for example, can be used as well as sodium lauryl sulfate. Tablets canbe coated with sugar as a flavor and sealant, or with film-formingprotecting agents to modify the dissolution properties of the tablet.The compositions can also be formulated as chewable tablets, forexample, by using substances such as mannitol in the formulation.

When it is desired to administer a DNAPK inhibitor as a suppository,typical bases can be used. Cocoa butter is a traditional suppositorybase, which can be modified by addition of waxes to raise its meltingpoint slightly. Water-miscible suppository bases comprising,particularly, polyethylene glycols of various molecular weights are inwide use.

The effect of the DNAPK inhibitor can be delayed or prolonged by properformulation. For example, a slowly soluble pellet of the DNAPK inhibitorcan be prepared and incorporated in a tablet or capsule, or as aslow-release implantable device. The technique also includes makingpellets of several different dissolution rates and filling capsules witha mixture of the pellets. Tablets or capsules can be coated with a filmthat resists dissolution for a predictable period of time. Even theparenteral preparations can be made long-acting, by dissolving orsuspending the DNAPK inhibitor in oily or emulsified vehicles that allowit to disperse slowly in the serum.

4.7 Kits

In certain embodiments, provided herein are kits comprising a DNAPKinhibitor.

In other embodiments, provide herein are kits comprising a DNAPKinhibitor and means for monitoring patient response to administration ofsaid DNAPK inhibitor. In certain embodiments, the patient has aWnt-associated cancer. In particular embodiments, the patient responsemeasured is inhibition of disease progression, inhibition of tumorgrowth, reduction of primary and/or secondary tumor(s), relief oftumor-related symptoms, improvement in quality of life, delayedappearance of primary and/or secondary tumors, slowed development ofprimary and/or secondary tumors, decreased occurrence of primary and/orsecondary tumors, slowed or decreased severity of secondary effects ofdisease, arrested tumor growth or regression of tumor.

In other embodiments, provided herein are kits comprising a DNAPKinhibitor and means for measuring markers of Wnt activity in a patient.In certain embodiments, the kits comprise means for measuring markers ofWnt activity in circulating blood or tumor cells and/or skin biopsies ortumor biopsies/aspirates of a patient. In certain embodiments, providedherein are kits comprising a DNAPK inhibitor and means for measuringmarkers of Wnt activity as assessed by comparison of the markers of Wntactivity before, during and/or after administration of the DNAPKinhibitor. In certain embodiments, provided herein are kits comprising aDNAPK inhibitor and means for measuring markers of DNAPK activity asassessed by comparison of the markers of DNAPK activity before, duringand/or after administration of the DNAPK inhibitor.

In certain embodiments, the kits provided herein further compriseinstructions for use, such as for administering a DNAPK inhibitor and/ormonitoring patient response to administration of a DNAPK inhibitor.

5. EXAMPLES 5.1 Biological Examples 5.1.1 DNAPK is the TopDifferentially Expressed Kinase Associated with Metastatic Progressionof CRPC

Association of expression of all known kinases with metastaticprogression in prostate cancer samples was examined in a cohort ofpatients treated with prostatectomy. Notable features of this cohortinclude the long clinical follow-up (median of 13.4 years), the largesample size (n=545), and the prevalence of high-risk characteristics asdefined by National Comprehensive Cancer Network criteria(www.nccn.org), such as extracapsular extension (50%) and seminalvesicle invasion (32%). Consistent with these features, 39% of thepatients experienced metastatic progression. In this discovery cohort,kinases were ranked by the relative enrichment for metastaticprogression in cases with high versus low expression of each kinase,with expression cut-offs defined by an unbiased clustering approach, asdescribed in methods. This analysis demonstrated that DNAPK was the topkinase that enriched for metastatic progression (OR=2.19, p<0.0001, FIG.1 (panel A)). The prognostic impact of elevated DNAPK expression inprostate cancer patients in this cohort showed that high DNAPK wassignificantly associated with not only metastatic progression (HR=2.0[1.5-2.7], p<0.0001), but also decreased rates of prostatecancer-specific survival (HR=2.4 [1.7-3.5], p<0.0001) and overallsurvival (HR=2.0 [1.5-2.6], p<0.0001) (FIG. 1 (panel B)). These findingswere validated in an independent cohort of patients where high DNAPKexpression again associated with increased metastatic progression(HR=2.4 [1.7-3.6], p<0.0001) and decreased prostate cancer-specificsurvival (HR=2 [1.1-3.5], p<0.02), with borderline significance fordecreased overall survival (HR=1.7 [0.97-2.8], p<0.06) (FIG. 1 (panelB)). After identifying the prognostic value of DNAPK in localizedprostate cancer, expression of DNAPK was examined in metastatic prostatecancer using Oncomine analysis (www.oncomine.org). DNAPK wassignificantly overexpressed in metastatic versus primary tumor prostatecancer samples in 10/12 cohorts (FIG. 1 (panel C)). These results showthat DNAPK is strongly prognostic in localized high-risk prostatecancer, and associated with the development of metastatic disease.

5.1.2 Effect of Knock Down or Inhibition of DNAPK on Aggressive CancerPhenotypes In Vitro

Knockdown (via siRNAs) or pharmacological inhibition (via the drugNU7441) of DNAPK drastically diminished the migration, invasion andproliferation of both AR-positive cells LNCaP-AR and C4-2, as well asAR-negative PC3 cells (FIG. 2 (panels A-D)). Efficient knockdown ofDNAPK was achieved in these experiments (FIG. 2 (panel E)). Thereduction in aggressive cancer phenotypes in AR-negative PC3 cellsindicated DNAPK has functions beyond regulating AR activity that maycontribute to oncogenic phenotypes in prostate cancer.

5.1.3 Effect of DNAPK on Wnt Signaling Pathway in Promotion ofAggressive Prostate Cancer

A list of genes that were significantly changed after DNAPK knockdown inVCaP, C4-2B, PC3 and DU145 cells by microarray and a list of genescorrelated with the DNAPK expression were generated based onguilt-by-association analyses in vitro and in vivo. GSEA of these genelists produced normalized enrichment scores (NES) for pathway gene sets.A scatterplot of gene set pathways was generated with in vitro NES valueon the y-axis, and with in vivo NES value on the x-axis (FIG. 3 (panelA)) as well as the greatest area under the curve (AUC=3.642). The Wntpathway had the top average NES (knockdown NES=1.48, NES=2.47,average=1.97, FIG. 3 (panel A)), and the most area under the curve(AUC=3.642). It was found that the expression of DNAPK was tightlycorrelated with the expression of beta catenin (Spearman's correlationcoefficient=0.71, FIG. 7 (panel A). These data demonstrated that Wntsignaling as a major pathway modulated by DNAPK, which is particularlyintriguing based on the established deregulation and oncogenic role ofWnt signaling in metastatic prostate cancer.

Higher expression of Wnt pathway genes across the cell line models ofdisease progression was found, with LNCaP cells representinghormone-sensitive disease (LNCaP-AR), C4-2B cells representingcastration-resistant prostate cancer (FIG. 3 (panel B)), andAR-independent PC3 cells representing neuro-endocrine component ofprostate cancer (FIG. 7 (panel B)). Consistent with the clinicalobservations that hormone naive cells eventually overcome the ADT, itwas found that LNCaP cells continued to grow despite hormone-depletion,albeit with a slower rate (FIG. 3 (panel C)). It was also found that thehormone-depletion triggered the expression of multiple Wnt genes inLNCaP cells, compared to LNCaP cells grown under normal serum conditions(FIG. 3 (panel D)). These data demonstrated that LNCaP cells are a goodmodel of Wnt signaling induction upon androgen deprivation.

5.1.4 Effect of Knock Down of DNAPK on Androgen-Depletion-Induced WntSignaling

It was observed that siRNA-mediated knockdown of DNAPK in LNCaP cellsgrown under hormone-depletion conditions abrogated the expression of Wntgenes (FIG. 3 (panel E)), indicating that DNAPK is required forADT-induced Wnt signaling.

5.1.5 Effect of DNAPK Inhibition on Wnt-Induced Cancer Phenotypes inCRPC Cells

A robust reduction of Wnt pathway genes after DNAPK silencing orinhibition in CRPC cells (LNCaP-AR and C4-2) (FIG. 4 (panels A-B) andFIG. 8 (panels A-B)) was found, while genes implicated in other pathway(i.e. notch) remain unchanged (FIG. 8 (panel C)). It was also found thatDNAPK knockdown or inhibition with NU7441 reduced baseline andWnt3A-induced levels of active beta-catenin and cMyc (a classical targetof Wnt signaling) (FIG. 4 (panels C-D)). Phenotypically, DNAPKinhibition with NU7441 or Compound 1 abrogated baseline andWnt3A-induced invasion and migration of CRPC cells (FIG. 4 (panel E)).These data indicate that Wnt signaling can drive oncogenic phenotypes inCRPC cells which can be blocked by DNAPK inhibition.

Increased expression of Wnt pathway genes in LNCaP-AR cells treated withlow-dose enzalutamide until resistance emerged (LNCaP-AR-MDVR; FIG. 9(panels A-B)) was also found. DNAPK inhibition with NU7441 or Compound 1significantly reduced invasion and migration of LNCaP-AR-MDVR cells(FIG. 4 (panel F)). Thus, DNAPK inhibition is a potential therapeuticstrategy in enzalutamide-resistant castration-resistant prostate cancer.Taken together, these data indicate that DNAPK inhibition is a highlypromising therapeutic strategy at critical points in prostate cancer: atADT initiation to prevent emergence of resistance, in ADT-resistantcastration-resistant prostate cancer, and after emergence ofenzalutamide resistance.

5.1.6 Wnt Signaling is a Major Target of DNAPK Inhibition

Co-immunoprecipitation studies revealed that DNAPK interacts with LEF1(FIG. 5 (panel A)), a major transcription factor of the Wnt pathway.DNAPK inhibition with NU7441 significantly reduced baseline andWnt3A-induced TOPFLASH reporter activity in PC3 cells (FIG. 5 (panelB)), indicating that DNAPK facilitates Wnt signaling through interactionwith the Wnt pathway transcription factor LEF1. Downregulation of Wntsignaling with siRNAs targeting LEF1 or beta-catenin (CTNNB1) resultedin substantial reduction in invasion and migration of LNCaP, C4-2, andPC3 cells (FIG. 5 (panel C)), almost comparable to reductions achievedwith DNAPK inhibition. These findings suggest that Wnt signalingblockade is a major component of the effects of DNAPK inhibition.

5.1.7 Effect of DNAPK Inhibition on CRPC Xenograft Growth In Vivo

Palpable LNCaP-AR tumors in castrated mice were treated with DNAPKinhibitor NU7441. There was a 44% reduction in tumor growth with NU7441treatment compared to control (relative tumor volume 4.84±1.97 withNU7441 vs 8.57±1.45 with vehicle, FIG. 6 (panels A-B)). This growthinhibition translated into a significant delay in tumor doubling time inthe NU7441 arm (median 21.5 days with NU7441 vs 7 days with vehicle,FIG. 6 (panel C)). The toxicity was minimal as measured by body weight(FIG. 10 (panel A)). Using a VCaP xenograft model, it was establishedthat Compound 1 induced a dose-dependent reduction in tumor growth, bestobserved at a non-toxic dose of 2 mg/kg (FIG. 10 (panels B-C). Theeffect of the same dose of Compound 1 on CRPC xenograft growth underpre-castrated conditions resulted in a significantly better tumorregression compared to enzalutamide (FIG. 6 (panel D)). A combination ofCompound 1 and enzalutamide resulted in a significant delay in tumorgrowth compared to either monotherapies. This reduction was associatedwith significant delay in tumor tripling time in the Compound1+enzalutamide arm, with median tumor tripling time of 38.5 days ascompared to vehicle (15 days), Compound 1 (29.5 days) or enzalutamide(23.5 days) (FIG. 6 (panel E)). DNAPK inhibition via Compound 1 alsoresulted in a significant regression of AR-independent PC3 tumors (FIG.10 (panel D)), confirming the potential of treatment strategies based onDNAPK inhibition in AR-independent disease. Consistent with thexenograft studies, human prostate cancer explants treated with NU7441showed marked reduction in Wnt target gene expression (FIG. 6 (panel F))and proliferative index, as determined by Ki67 levels (FIG. 6 (panelG)). Taken together, our results highlight the promise of DNAPKinhibition in the treatment of aggressive prostate cancer.

A number of references have been cited, the disclosures of which areincorporated herein by reference in their entirety. The embodimentsdisclosed herein are not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the disclosed embodiments and anyembodiments that are functionally equivalent are encompassed by thepresent disclosure. Indeed, various modifications of the embodimentsdisclosed herein are in addition to those shown and described hereinwill become apparent to those skilled in the art and are intended tofall within the scope of the appended claims.

1. A method for treating or preventing a Wnt-associated cancer,comprising administering an effective amount of a DNAPK inhibitor to apatient having a Wnt-associated cancer, wherein the DNAPK inhibitor is acompound of formula (I):

or a pharmaceutically acceptable salt, clathrate, solvate, stereoisomer,tautomer, metabolite, isotopologue or prodrug thereof, wherein: R¹ issubstituted or unsubstituted C₁₋₈ alkyl, substituted or unsubstitutedaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, or substituted or unsubstitutedheterocyclylalkyl; R² is H, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aralkyl, or substituted or unsubstitutedcycloalkylalkyl; R³ is H, or a substituted or unsubstituted C₁₋₈ alkyl.2. The method of claim 1, wherein the Wnt-associated cancer is gastriccancer, breast cancer, endometrial cancer, uterine cancer, colorectalcancer, synovial sarcoma, pancreatic cancer, melanoma, lobularcarcinoma, prostate cancer, triple negative breast cancer (TNBC),non-small cell lung cancer (NSCLC), squamous cell lung carcinoma, lungadenocarcinoma, hepatocellular cancer (HCC), ovarian cancer, adenoidcarcinoma, adrenocortical carcinoma, bladder/urothelial carcinoma,glioblastoma multiforme (GBM), cervical cancer, head and neck squamouscell carcinoma (HNSCC), kidney cancer, thyroid cancer, acute myelogenousleukemia (AML), acute lymphoblastic leukemia (ALL), multiple myeloma(MM), chronic lymphocytic leukemia (CLL), or chronic myelogenousleukemia.
 3. The method of claim 1, wherein said patient is administeredabout 0.5 mg/day to about 128 mg/day of the DNAPK inhibitor.
 4. Themethod of claim 1, wherein said patient is administered 0.5 mg/day, 1mg/day, 2 mg/day, 4 mg/day, 8 mg/day, 16 mg/day, 20 mg/day, 30 mg/day,45 mg/day, 60 mg/day, 90 mg/day, 120 mg/day or 128 mg/day of the DNAPKinhibitor.
 5. The method of claim 1, wherein said patient isadministered a unit dosage form comprising 0.25 mg, 1.0 mg, 5.0 mg, 7.5mg, or 10 mg of the DNAPK inhibitor.
 6. The method of claim 1, furthercomprising administering a Wnt pathway modulator, a Wnt inhibitor or anAR antagonist
 7. (canceled)
 8. The method of claim 1, wherein the DNAPKinhibitor is not


9. The method of claim 1, wherein the DNAPK inhibitor is:7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(cis-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((cis-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-ethyl-7-(1H-pyrrolo[3,2-b]pyridin-5-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((cis-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-benzo[d]imidazol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((trans-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(cis-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(cis-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-ethyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((cis-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-indol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((trans-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((cis-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(trans-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(trans-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-ethyl-7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-hydroxypyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-isopropyl-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;5-(8-isopropyl-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide;7-(1H-indazol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-aminopyrimidin-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-aminopyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(methylamino)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-hydroxypyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(4-(1H-pyrazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(pyridin-3-yl)-1(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-indazol-4-yl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-indazol-6-yl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(pyrimidin-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-methoxypyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(2-methoxyethyl)-7-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-ethyl-7-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-ethyl-7-(1H-indazol-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(pyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-aminopyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-methyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;2-(2-hydroxypropan-2-yl)-5-(8-(trans-4-methoxycyclohexyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)pyridine1-oxide;4-methyl-5-(7-oxo-8-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)picolinamide;5-(8-((cis-4-methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide;7-(1H-pyrazol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(trans-4-methoxycyclohexyl)-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;3-((7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-2-oxo-3,4-dihydropyrazino[2,3-b]pyrazin-1(2H)-yl)methyl)benzonitrile;1-((trans-4-methoxycyclohexyl)methyl)-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;3-(7-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)benzamide;5-(8-((trans-4-methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide;3-((7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-oxo-3,4-dihydropyrazino[2,3-b]pyrazin-1(2H)-yl)methyl)benzonitrile;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1R,3R)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1S,3R)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1 S,3S)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1R,3S)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-indazol-6-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-morpholinoethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(trans-4-hydroxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(cis-4-hydroxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-morpholinoethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-isopropyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-imidazo[4,5-b]pyridin-6-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-((cis-4-methoxycyclohexyl)methyl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(trans-4-hydroxycyclohexyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(cis-4-hydroxycyclohexyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;4-(7-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)benzamide;7-(1H-indazol-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-((1S,3R)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-((1R,3R)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-((1R,3S)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-((1 S,3S)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-indol-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-indol-6-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(4-(2-hydroxypropan-2-yl)phenyl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-((trans-4-methoxycyclohexyl)methyl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((cis-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(2-methoxyethyl)-7-(4-methyl-2-(methylamino)-1H-benzo[d]imidazol-6-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(7-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(2-methoxyethyl)-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-benzyl-7-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(3-fluoro-4-(4H-1,2,4-triazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(3-fluoro-4-(4H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(3-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(trans-4-methoxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(3-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(2-methoxyethyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(cyclopentylmethyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(4-(2-hydroxypropan-2-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;(S)-7-(6-(1-hydroxyethyl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;(R)-7-(6-(1-hydroxyethyl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(4-(2-hydroxypropan-2-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(4-(trifluoromethyl)benzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(3-(trifluoromethyl)benzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(3-methoxypropyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(4-methyl-2-(methylamino)-1H-benzo[d]imidazol-6-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-amino-4-methyl-1H-benzo[d]imidazol-6-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;(R)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-methyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;(S)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-methyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,3-dimethyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-amino-4-methyl-1H-benzo[d]imidazol-6-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(4-(1H-1,2,4-triazol-5-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(1-hydroxypropan-2-yl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;or1-(2-hydroxyethyl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one,or a pharmaceutically acceptable salt, clathrate, solvate, stereoisomer,tautomer, metabolite, isotopologue or prodrug thereof.
 10. The method ofclaim 1, wherein the DNAPK inhibitor is1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one,or a tautomer thereof, for example,1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one,or1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one.